Background: 74% of breast cancer patients were diagnosed with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative tumors. These patients have excellent survival, but their risk of distant recurrence persists for up to 20 years. Recent clinical trials have found that 10 years of endocrine therapy reduced the recurrence rate and breast cancer mortality when compared to 5 years of endocrine therapy. Accordingly, the American Society of Clinical Oncology (ASCO) recently updated the clinical practice guidelines to recommend the extension of endocrine therapy from 5 to 10 years for ER- positive, recurrence-free patients after 5 years of endocrine therapy. While the current guidelines are evidence- based, oncologists are left with insufficient data to identify patients with the most favorable benefit to harm profile for extended endocrine therapy use. Objective: This application proposes the use of simulation modeling to assess the personalized balance of benefits and harms of 5 vs. 10 years of endocrine therapy based on combinations of the patient's tumor characteristics and joint distributions of (1) age, (2) comorbidity, (3) adverse events, (4) predicted recurrence risk, and (5) patient preferences. Specific Aims: The aims of the proposed research are Aim 1: Quantify the personalized benefits and harms of 5 vs. 10 years of endocrine therapy in individual patients based on combinations of the patient's tumor characteristics and joint distributions of (1) age, (2) comorbidity, (3) adverse events, (4) predicted recurrence risk, and (5) patient preferences. Aim 2: Test how treatment adherence might affect the balance of benefits and harms of 5 vs. 10 years of endocrine therapy in the aforementioned patients with different tumor features and personal characteristics. Aim 3: Explore how the balance of benefits and harms of 5 vs. 10 years of endocrine therapy will shift if a new hypothetical gene expression profiling test can have better predictive performance for distant recurrence in 1-10 year and 11-20 years post diagnosis. Study Design: This proposed research will adapt a well-established simulation model in order to synthesize available evidence sources with the goal of informing decisions about extended endocrine therapy. Each projected outcomes will show point estimate (mean or median) of the simulated probability, range of 95% confidence interval, and distribution over 25 years. Implications of Results for Translation: This proposed research will fill important gaps in current clinical decision tools for the estimated 185,000 ER+ patients diagnosed each year with invasive, non-metastatic breast cancer. The model and its results will be immediately useful to clinical practice. The model can also be used in future research as the back-engine to develop a computerized or web-based clinical decision tool to determine a personalized balance of benefits and harms of 5 vs. 10 years of endocrine therapy.